THE SPINAL CONTRIBUTION OF SUBSTANCE-P TO THE GENERATION AND MAINTENANCE OF INFLAMMATORY HYPERALGESIA IN THE RAT

That substance P (SP) contributes in some way to spinal nociceptive pr ocessing has been known for many years. However, the contribution of S P and NK-1 receptors to the generation and maintenance of inflammatory hyperalgesia or persistent chemical hyperalgesia is not clear. The pu rpose of this study was to test the hypothesis that SP contributes to the generation but not maintenance of hyperalgesia using two models of inflammatory pain: carrageenan, which allows for testing of acute nox ious thermal and mechanical stimuli, and formalin, a model of spontane ous pain. Intrathecal pretreatment with the NK-1 receptor antagonist C P-96,345 (100, 50, 25 nmol) dose-dependently attenuated the thermal (4 6%, 27% and 16%, respectively) and mechanical (66%, 37% and 3%, respec tively) hyperalgesia produced by 2 mg carrageenan, but not 6 mg carrag eenan, 3 h after the induction of inflammation. The attenuation was st ill apparent at 5 h for the greatest dose, but at 7 h the magnitude of hyperalgesia was equal to rats pretreated with saline. Posttreatment with 100 nmol CP-96,345 following the establishment of hyperalgesia ha d no effect. Intrathecal pretreatment with 125 nmol CP-96,345 prior to formalin (1% or 5%) injection into the hindpaw produced an overall 29 % or 23% attenuation, respectively, of the nociceptive behavior during the l-h observation period. For both 1% and 5% formalin injections, t he phase 2 response, but not the phase 1 response, was significantly w ith saline. Pretreatment with 100 or 125 nmol of the inactive enantiom er, CP- 96,344, was no different than pretreatment with saline. A dose of 250 nmol CP-96,345 produced voluntary paralysis yet the flexion re flex to noxious pinch remained. These results support the hypothesis t hat SP contributes to the generation of inflammatory hyperalgesia but once established, the contribution of SP to maintaining the state of h yperalgesia is reduced. The interaction of SP, NK-1 receptors and spin al NMDA receptors in relation to inflammatory pain is discussed.